The role of RNF138 in DNA end resection is regulated by ubiquitylation and CDK phosphorylation.

Double-strand breaks (DSBs) are DNA lesions that pose a significant threat to genomic stability. The repair of DSBs by the homologous recombination (HR) pathway is preceded by DNA end resection, the 5' to 3' nucleolytic degradation of DNA away from the DSB. We and others previously identified a role for RNF138, a really interesting new gene finger E3 ubiquitin ligase, in stimulating DNA end resection and HR. Yet, little is known about how RNF138's function is regulated in the context of DSB repair. Here, we show that RNF138 is phosphorylated at residue T27 by cyclin-dependent kinase (CDK) activity during the S and G2 phases of the cell cycle. We also observe that RNF138 is ubiquitylated constitutively, with ubiquitylation occurring in part on residue K158 and rising during the S/G2 phases. Interestingly, RNF138 ubiquitylation decreases upon genotoxic stress. By mutating RNF138 at residues T27, K158, and the previously identified S124 ataxia telangiectasia mutated phosphorylation site (Han et al., 2016, ref. 22), we find that post-translational modifications at all three positions mediate DSB repair. Cells expressing the T27A, K158R, and S124A variants of RNF138 are impaired in DNA end resection, HR activity, and are more sensitive to ionizing radiation compared to those expressing wildtype RNF138. Our findings shed more light on how RNF138 activity is controlled by the cell during HR.

SUMOylation mediates CtIP's functions in DNA end resection and replication fork protection.

Double-strand breaks and stalled replication forks are a significant threat to genomic stability that can lead to chromosomal rearrangements or cell death. The protein CtIP promotes DNA end resection, an early step in homologous recombination repair, and has been found to protect perturbed forks from excessive nucleolytic degradation. However, it remains unknown how CtIP's function in fork protection is regulated. Here, we show that CtIP recruitment to sites of DNA damage and replication stress is impaired upon global inhibition of SUMOylation. We demonstrate that CtIP is a target for modification by SUMO-2 and that this occurs constitutively during S phase. The modification is dependent on the activities of cyclin-dependent kinases and the PI-3-kinase-related kinase ATR on CtIP's carboxyl-terminal region, an interaction with the replication factor PCNA, and the E3 SUMO ligase PIAS4. We also identify residue K578 as a key residue that contributes to CtIP SUMOylation. Functionally, a CtIP mutant where K578 is substituted with a non-SUMOylatable arginine residue is defective in promoting DNA end resection, homologous recombination, and in protecting stalled replication forks from excessive nucleolytic degradation. Our results shed further light on the tightly coordinated regulation of CtIP by SUMOylation in the maintenance of genome stability.

Post-dural puncture headache: a prospective study on incidence, risk factors, and clinical characterization of 285 consecutive procedures.

BACKGROUND: Lumbar puncture (LP) is a common and relatively safe neurological procedure. It can be complicated by post-dural puncture headache (PDPH) after both diagnostic and therapeutic procedures. The aim of this study is to identify the incidence, risk factors and clinical characterization of PDPH in the inpatient setting of the main tertiary neurology hospital in Kuwait. METHODS: We conducted a prospective observational cohort study that included patients who were admitted to neurology department at Ibn Sina hospital, Kuwait, from January 1, 2019 to December 31, 2020, on whom, LP was performed for diagnostic and/or therapeutic reasons. Multivariate logistic regression analysis was performed to evaluate the association between PDPH and different clinical parameters. RESULTS: A total of 285 patients were included; 225 females (78.9%), mean age of 32.9 ± 11.7 years. PDPH was reported by 84 patients (29.5%), with mean headache onset of 1.7 ± 0.8 days, and mean duration of 2.4 ± 2.1 days. The commonest headache type was dull aching in 49 patients (58.3%). Headache severity was mild to moderate in 64 patients (76.2%), with mean NRS of 4.1 ± 0.9. Most PDPH (99.3%) resolved with conservative medical management, with only 2 patients (0.7%) requiring epidural blood patch. In multivariate logistic regression model, there was a statistically significant correlation between development of PDPH and young age (p = 0.001), female gender (p = 0 .001), low BMI (p < 0 .001), pre-LP headache (p = 0.001), history of previous PDPH (p = 0.001), and number of LP attempts (p < 0.001). PDPH was statistically significantly higher in patients with optic neuritis (p = 0.009), and cerebral venous thrombosis (p = 0.007), and lower in patients with peripheral neuropathy (p = 0.011) and spinal muscular atrophy (p = 0.042). CONCLUSIONS: Findings from clinical practice in the main tertiary neurology hospital in Kuwait were in line with literature findings. Younger age, female gender, lower BMI, pre-procedural headache, previous history of PDPH, and number of LP attempts were found to be independent risk factors for developing PDPH. To our knowledge, this study represents the first comprehensive description of PDPH in a population from the Arabian Gulf Region.

The Effect of Interleukin-6 and Tumor Necrosis Factor-Alpha Gene Polymorphism and Hormone Replacement Therapy on Polycystic Ovary Syndrome.

PCOS (polycystic ovarian syndrome) is a prevalent and complicated gynecological endocrine disease that affects around 6% to 10% of women of reproductive age. PCOS is marked by oligoanovulation or anovulation, hyperandrogenism, hyperinsulinemia, monthly irregularity, and infertility. This study included 58 Kurdish females with PCOS who went to private clinics at Hawler city. The disease was confirmed by the doctors with laboratory results and US checking. They were at different age groups with different marital statuses. Demographic distribution, hormonal level and hormone replacement therapy were measured. Cytokine gene polymorphisms were evaluated by Single nucleotide polymorphism (SNP). The amplification-refractory mutation system (ARMS) was used to determine the gene polymorphisms. There was a significant change in the hormone levels and the medications as hormone replacement therapy gained best results for impregnation of the patients by Progyluton, Diane35 with metformin. Results of genetic variations in the evaluated cytokines revealed that for IL-6-174GC polymorphism the CC genotype was considered as a risk factor with OR:1.58, CI:0.16-15.36. While for TNF-α the higher producer GG genotype was the most susceptible cause of the disease with OR:1.41, CI: 0.59-3.36. Data of this study indicated the positive relationship between IL-6 -174GC polymorphism with PCOS while no association was detected for TNF-α -308GA.

How important is income in explaining individuals having forgone healthcare due to cost-sharing payments? Results from a mixed methods sequential explanatory study.

BACKGROUND: Patients having forgone healthcare because of the costs involved has become more prevalent in recent years. Certain patient characteristics, such as income, are known to be associated with a stronger demand-response to cost-sharing. In this study, we first assess the relative importance of patient characteristics with regard to having forgone healthcare due to cost-sharing payments, and then employ qualitative methods in order to understand these findings better. METHODS: Survey data was collected from a Dutch panel of regular users of healthcare. Logistic regression models and dominance analyses were performed to assess the relative importance of patient characteristics, i.e., personal characteristics, health, educational level, sense of mastery and financial situation. Semi-structured interviews (n = 5) were conducted with those who had forgone healthcare. The verbatim transcribed interviews were thematically analyzed. RESULTS: Of the 7,339 respondents who completed the questionnaire, 1,048 respondents (14.3%) had forgone healthcare because of the deductible requirement. The regression model indicated that having a higher income reduced the odds of having forgone recommended healthcare due to the deductible (odds ratios of higher income categories relative to the lowest income category (reference): 0.29-0.49). However, dominance analyses revealed that financial leeway was more important than income: financial leeway contributed the most (34.8%) to the model's overall McFadden's pseudo-R2 (i.e., 0.123), followed by income (25.6%). Similar results were observed in stratified models and in population weighted models. Qualitative analyses distinguished four main themes that affected the patient's decision whether to use healthcare: financial barriers, structural barriers related to the complex design of cost-sharing programs, individual considerations of the patient, and the perceived lack of control regarding treatment choices within a given treatment trajectory. Furthermore, "having forgone healthcare" seemed to have a negative connotation. CONCLUSION: Our findings show that financial leeway is more important than income with respect to having forgone recommended healthcare due to cost-sharing payments, and that other factors such as the perceived necessity of healthcare also matter. Our findings imply that solely adapting cost-sharing programs to income levels will only get one so far. Our study underlines the need for a broader perspective in the design of cost-sharing programs.

The Role of DNA Repair in Genomic Instability of Multiple Myeloma.

Multiple Myeloma (MM) is a B cell malignancy marked by genomic instability that arises both through pathogenesis and during disease progression. Despite recent advances in therapy, MM remains incurable. Recently, it has been reported that DNA repair can influence genomic changes and drug resistance in MM. The dysregulation of DNA repair function may provide an alternative explanation for genomic instability observed in MM cells and in cells derived from MM patients. This review provides an overview of DNA repair pathways with a special focus on their involvement in MM and discusses the role they play in MM progression and drug resistance. This review highlights how unrepaired DNA damage due to aberrant DNA repair response in MM exacerbates genomic instability and chromosomal abnormalities, enabling MM progression and drug resistance.

Nanoinhibitory Impacts of Salicylic Acid, Glycyrrhizic Acid Ammonium Salt, and Boric Acid Nanoparticles against Phytoplasma Associated with Faba Bean.

Phytoplasmas are economically important plant pathogenic bacterial diseases, causing severe yield losses worldwide. In this study, we tested nanoformulations such as glycyrrhizic acid ammonium salt (GAS), salicylic acid (SA), and boric acid (BA) as novel antimicrobial agents inducing the resistance against the phytoplasma disease in faba bean. The nanoparticles (NP) were foliar-applied to naturally phytoplasma-infected faba bean with three concentrations from each of SA, GAS, and BA, under field conditions. Nested PCR (using universal primer pairs P1/P7 and R16F2n/R16R2) were reacted positively with all symptomatic samples and gave a product size of approximately 1200 bp, while the healthy plant gave no results. Transmission electron microscopy examinations of phytoplasma-infected faba bean plants treated with different nanoparticles revealed that severe damage occurred in phytoplasma particle's structure, degradation, malformation, lysis in the cell membrane, and the cytoplasmic leakage followed by complete lysis of phytoplasma cells. Exogenous application of GAS-NP (1.68 µM), SA-NP (0.28 µM), and BA-NP (0.124 µM) suppressed the infection percentage of phytoplasma by 75%, 50%, and 20%, and the disease severity by 84%, 64%, and 54%, respectively. Foliar application of nanoparticles improved Fv/Fm (maximum quantum efficiency of PSII Photochemistry), PI (the performance index), SPAD chlorophyll (the relative chlorophyll content), shoots height, and leaves number, thus inducing recovery of the plant biomass and green pods yield. The most effective treatment was GAS-NP at 1.68 µM that mediated substantial increases in the shoots' fresh weight, shoots' dry weight, number of pods per plant, and green pods yield by 230%, 244%, 202% and 178%, respectively, compared to those of infected plants not sprayed with nanoparticles. This study demonstrated the utility of using nanoparticles, particularly GAS-NP at 1.68 µM to suppress the phytoplasma infection.

Nanobiotechnological Approaches to Enhance Drought Tolerance in Catharanthus roseus Plants Using Salicylic Acid in Bulk and Nanoform.

Drought has a detrimental effect on crop production, affecting economically important plants' growth rates and development. Catharanthus roseus is an important medicinal plant that produces many pharmacologically active compounds, some of which have significant antitumor activity. The effect of bulk salicylic acid (SA) and salicylic acid nanoparticles (SA-NPs) were evaluated on water-stressed Catharanthus roseus plants. The results showed that SA and SA-NPs alleviated the negative effects of drought in the treated plants by increasing their shoot and root weights, relative water content, leaf area index, chlorophyll content, and total alkaloids percentage. From the results, a low concentration (0.05 mM) of SA-NPs exerted positive effects on the treated plants, while the best results of the bulk SA were recorded after using the highest concentration (0.1 mM). Both treatments increased the expression level of WRKY1, WRKY2, WRKY40, LEA, and MYC2 genes, while the mRNA level of MPKK1 and MPK6 did not show a significant change. This study discussed the importance of SA-NPs in the induction of drought stress tolerance even when used in low concentrations, in contrast to bulk SA, which exerts significant results only at higher concentrations.

Use of Pulsed Lavage Reduces the Rate of Surgical Site Infection After Laparotomy.

INTRODUCTION: Surgical site infections (SSI) are a preventable and common post-operative complication within general surgery. Intra-operative irrigation of surgical incisions is an inexpensive method to reduce post-operative SSI rates, however its use is predominantly limited to orthopaedic surgery. We aimed to assess the effects of pulsed lavage (PL) irrigation on SSI rates following elective and emergency laparotomies. METHODS: Elective and emergency patients who underwent a laparotomy between 2018 and 2019 were included. Relevant demographic and peri-operative risk factors collected retrospectively, following strengthening the reporting of observational studies in epidemiology (STROBE) criteria. The primary outcome was rate of superficial SSI within 30 days of the operation. Independent risk factors were assessed via multivariate logistic regression analysis. RESULTS: 176 patients were identified, with an average age of 60.7 ± 19.1 y. 82.4% (145/176) were emergencies and the mean ASA grade was 2.8. Fifty-two patients (29.5%) had PL used during their operation. Thirty-seven patients (29.8%, 37/124) in the control group developed a SSI, compared to seven patients (13.5%, 7/52) in the PL group (P = 0.022). At multi-variate analysis, the use PL conferring an Odds Ratio 0.36 (CI 0.12-0.94, P= 0.047) for developing a SSI. CONCLUSION: PL appears to significantly reduced the rate of SSI following laparotomy. There remains scope to reduce the incidence of this common and expensive post-operative complication, and PL could provide a potential cost-effective means to deliver improved outcomes. Future prospective randomised trials are essential to fully assess its benefits and wider use within general surgery.

Biosynthesis of silver nanoparticles by Nocardiopsis sp.-MW279108 and its antimicrobial activity.

The utilization of microorganisms like bacteria in the biological synthesis of silver nanoparticles (AgNPs) has attracted widespread attention due to their ability to synthesize different shape sizes, states, and morphology nanoparticles. In the current study, the green synthesis of AgNPs by Nocardiopsis sp. 16S ribosomal RNA analysis was used to characterize the Nocardiopsis sp. The synthesized AgNPs were characterized through multi-instrument platforms such as transmission electron microscopy (TEM), Fourier transform infrared spectroscopy (FTIR), UV-Vis spectroscopy, scanning electron microscope (SEM), and X-ray diffraction analysis (XRD). The antimicrobial activity of the synthesized AgNPs was determined by the agar plate diffusion method. The UV-Vis absorbance analysis of the synthesized AgNPs has a significant absorbance at 384 nm, confirming the AgNPs' surface plasmon resonance. The SEM and TEM characterizations indicate that the particle size ranges from 2 to 10 nm and is spherical. Additionally, the FTIR spectra revealed bands from 476 to 3819cm-1 , respectively. The XRD planes study pronounced strong bands ranging are between 111 and 311 corresponding to cubic face-center of the silver. Also, the antimicrobial activity of AgNPs indicated the biogenic AgNPs could control the growth of the clinical isolates. The AgNPs produced by Nocardiopsis sp. supernatant could be used in different nanomedicinal applications.

The Role of Polycomb Group Protein BMI1 in DNA Repair and Genomic Stability.

The polycomb group (PcG) proteins are a class of transcriptional repressors that mediate gene silencing through histone post-translational modifications. They are involved in the maintenance of stem cell self-renewal and proliferation, processes that are often dysregulated in cancer. Apart from their canonical functions in epigenetic gene silencing, several studies have uncovered a function for PcG proteins in DNA damage signaling and repair. In particular, members of the poly-comb group complexes (PRC) 1 and 2 have been shown to recruit to sites of DNA damage and mediate DNA double-strand break repair. Here, we review current understanding of the PRCs and their roles in cancer development. We then focus on the PRC1 member BMI1, discussing the current state of knowledge of its role in DNA repair and genome integrity, and outline how it can be targeted pharmacologically.

Expression of CXCR7 in colorectal adenoma and adenocarcinoma: Correlation with clinicopathological parameters.

Colorectal carcinoma (CRC) is one of the most lethal malignancies, it ranks third in cancer-related morbidity and mortality. Although great progress has been made in early diagnosis and combined treatment of CRC, the prognosis of patients remains poor owing to the high rate of recurrence and distant metastasis. CXCR7 belongs to chemokine receptor family and has been identified as a novel receptor for CXCL12. It plays an important role in development and in progression of cancer to metastatic stage. THE AIM OF STUDY: To evaluate the immunohistochemical expression of CXCR7 in colorectal adenoma and carcinoma and to analyze its correlation with clinicopathological factors. This is retrospective study including 58 colonic adenocarcinoma specimens and 18 cases of colonic adenoma. RESULTS: CXCR7 showed positive cytoplasmic expression in two out 18 cases of colorectal adenoma (11%) and 42 out of 58 cases of CRC (72.4%) with a significant difference between both (p < 0.001). We found a significant correlation between upregulation of CXCR7 and presence of lymphovascular tumor emboli, presence of lymph node metastasis and advanced TNM stage of the CRC. The association of the CXCR7 with patient age, sex, tumor size, depth of invasion and tumor cell differentiation was found to be non-significant. Regarding colonic adenoma, we found no significant association between CXCR7 expression on one hand and patient age, sex, tumor size, histologic type and degree of dysplasia on the other hand. CONCLUSION: CXCR7 in CRC may act as a novel predictive indicator for prognosis and even be a potential molecular target for anticancer therapies.

A Fast-Response Red Shifted Fluorescent Probe for Detection of H2S in Living Cells.

Near-infrared (NIR) fluorescent probes are attractive tools for bioimaging applications because of their low auto-fluorescence interference, minimal damage to living samples, and deep tissue penetration. H2S is a gaseous signaling molecule that is involved in redox homeostasis and numerous biological processes in vivo. To this end, we have developed a new red shifted fluorescent probe 1 to detect physiological H2S in live cells. The probe 1 is based on a rhodamine derivative as the red shifted fluorophore and the thiolysis of 7-nitro 1,2,3-benzoxadiazole (NBD) amine as the H2S receptor. The probe 1 displays fast fluorescent enhancement at 660 nm (about 10-fold turn-ons, k2 = 29.8 M-1s-1) after reacting with H2S in buffer (pH 7.4), and the fluorescence quantum yield of the activated red shifted product can reach 0.29. The probe 1 also exhibits high selectivity and sensitivity towards H2S. Moreover, 1 is cell-membrane-permeable and mitochondria-targeting, and can be used for imaging of endogenous H2S in living cells. We believe that this red shifted fluorescent probe can be a useful tool for studies of H2S biology.

Efficacy of some feed additives to attenuate the hepato-renal damage induced by aflatoxin B1 in rabbits.

The present trial was conducted to evaluate the beneficial role of some feed additives (potassium sorbate; Sor, hydrated sodium calcium almuniosilicate; Hsc and l-methionine; L-M) in attenuating the hepatic and renal toxicity of aflatoxin B1 (AFB1) in rabbits. A total number of 72 NZW growing rabbits (5 week-old) were divided into six experimental groups (four replicates with three rabbits each) as follows: control group, AFB1 group (supplemented with AFB1 0.3 mg/kg diet), AFB1 + Sor group (AFB1 0.3 mg/kg diet + Sor 2 g/kg diet), AFB1 + Hsc group (AFB1 0.3 mg/kg diet + Hsc 5 g/kg diet), AFB1 + L-M group (AFB1 0.3 mg/kg diet + L-M 8 g/kg diet) and AFB1 + Mix group (AFB1 0.3 mg/kg diet + 2 Sor + 5 Hsc + 8 L-M g/kg diet). Serum levels of total protein, albumin and globulin were significantly reduced by AF. AF increased the serum activity of aspartate aminotransferase (AST), alanine amino transferase (ALT) and alkaline phosphatase (ALP) enzymes. While, they were reduced in AF + Sor and AF + Mix groups compared with AF group. AF increased the level of cystatin C and Beta-2 microglobulin (BMG). All other supplements significantly reduced the level of cystatin C than AF; however, this reduction was more pronounced in AF-L-M group. AF + Sor, AF + L-M and AF + Mix equally reduced the BMG level than AF and AF + HSc, however, still higher than control. AF elevated the total cholesterol (TC) and LDL-cholesterol levels. A significant reduction in HDL cholesterol was seen in AF group. Additionally, AF induced pathological alterations in the liver and kidney of exposed rabbits on the other hands, the three additives separately or in mix attenuated the Af-induced alterations. In conclusion, the dietary supplementation of Sor, L-M, Hsc or their mixture was effective in ameliorating the negative effects of AFB1 on liver and kidney function and structure in rabbits with more better improvement obtained by Sor or L-M separately.

Dietary supplementation of potassium sorbate, hydrated sodium calcium almuniosilicate and methionine enhances growth, antioxidant status and immunity in growing rabbits exposed to aflatoxin B1 in the diet.

The present experiment was conducted to evaluate the effect of dietary supplementation with some feed additives (potassium sorbate; Sor, hydrated sodium calcium almuniosilicate; Hsc and L-methionine; L-M) against aflatoxin B1 (AF) toxicity in rabbits. A total of 72 growing rabbits (5-week-old) were distributed into six equal groups (4 replicates with 3 rabbits each). The experimental groups are as follows: control group, AF group (supplemented with AF 0.3 mg/kg diet), AF + Sor group (AF 0.3 mg/kg diet + Sor 2 g/kg diet), AF + Hsc group (AF 0.3 mg/kg diet + Hsc 5 g/kg diet), AF + L-M group (AF 0.3 mg/kg diet + L-M 8 g/kg diet) and AF + Mix group (AF 0.3 mg/kg diet + 2 Sor + 5 Hsc + 8 L-M g/kg diet). Live body weight and weight gain at 13 weeks of age were significantly reduced by AF. Feed intake at 13 weeks of age was decreased in AF, AF + Hsc and AF + Mix compared to the control. AF, AF + Hsc and AF + Mix showed the lowest total antioxidant capacity compared to the control. The highest level of reactive oxygen species and 8-Hydroxy-2-desoxyguanosine was observed in AF group. Using of other supplements with AF increased immunoglobulinM than AF alone. In conclusion, dietary supplementation of Sor, L-M, Hsc or their mixture was effective in reducing the adverse effects of AF on performance, antioxidant and immune status of rabbits with more better improvement obtained by Sor or L-M separately.

Impact of coronavirus disease 2019 (COVID-19) pandemic on patients with migraine: a web-based survey study.

BACKGROUND: Since the declaration COVID-19 as a pandemic, healthcare systems around the world have faced a huge challenge in managing patients with chronic diseases. Patients with migraine were specifically vulnerable to inadequate medical care. We aimed to investigate the "real-world" impact of COVID-19 pandemic on migraine patients, and to identify risk factors for poor outcome. METHODS: We administered an online, self-reported survey that included demographic, migraine-related, COVID-19-specific and overall psychosocial variables between July 15 and July 30, 2020. We recruited a sample of patients with migraine from headache clinic registry and via social media to complete an anonymous survey. Outcomes included demographic variables, change in migraine frequency and severity during the lockdown period, communication with treating physician, compliance to migraine treatment, difficulty in getting medications, medication overuse, symptoms of anxiety and/or depression, sleep and eating habits disturbance, screen time exposure, work during pandemic, use of traditional medicine, effect of Botox injection cancellation, and overall worries and concerns during pandemic. RESULTS: A total of 1018 patients completed the survey. Of the respondents, 859 (84.3%) were females; 733 (71.9%) were aged 20 to 40 years, 630 (61.8%) were married, and 466 (45.7%) reported working during the pandemic. In comparison to pre-pandemic period, 607 respondents (59.6%) reported increase in migraine frequency, 163 (16%) reported decrease in frequency, and 105 (10.3%) transformed to chronic migraine. Severity was reported to increase by 653 (64.1%) respondents. The majority of respondents; 626 (61.5%) did not communicate with their neurologists, 477 (46.9%) reported compliance to treatment, and 597 (58.7%) reported overuse of analgesics. Botox injections cancellation had a negative impact on 150 respondents (66.1%) from those receiving it. Forty-one respondents (4%) were infected with COVID-19; 26 (63.4%) reported worsening of their headaches amid infection period. Sleep disturbance was reported by 794 (78.1%) of respondents, and 809 (79.5%) reported having symptoms of anxiety and/or depression. CONCLUSIONS AND RELEVANCE: COVID-19 pandemic had an overall negative impact on patients with migraine. Several risk factors for poor outcome were identified. Long-term strategies should be validated and implemented to deliver quality care for patients with migraine, with emphasis on psychosocial well-being.

Melatonin inhibits breast cancer cell invasion through modulating DJ-1/KLF17/ID-1 signaling pathway.

Breast cancer is the most common neoplastic disorder diagnosed in women. The main goal of this study was to explore the effect of melatonin against breast cancer metastasis and compared this with the actions of taxol (a well-known chemotherapeutic drug), and the impact of their combination against breast cancer metastasis. Melatonin showed no cytotoxic effect while taxol showed antiproliferative and cytotoxic effects on MCF-7 and MDA-MB-231 cells. Furthermore, melatonin inhibited the generation of reactive oxygen species. Melatonin and taxol clearly decreased cell migration and invasion at low doses, especially those matching the normal physiological concentration at night. Melatonin and taxol markedly reduced DJ-1 and ID-1 and increased KLF17 messenger RNA and protein expression levels. The present results also showed that melatonin and taxol induced GSK3-ß nuclear and Snail cytosolic localization. These changes were accompanied by a concurrent rise in E-cadherin expression. The above data show that normal levels of melatonin may help in preventing breast cancer metastasis through inhibiting DJ-1/KLF17/ID-1 signaling pathway. The combination of melatonin and taxol is a potent candidate against breast cancer metastasis, better than using melatonin or taxol as a single drug.

A fluorogenic H2S-triggered prodrug based on thiolysis of the NBD amine.

Based on thiolysis of the NBD amine, a H2S-triggered prodrug has been designed and synthesized for localized production of ciprofloxacin under micromolar H2S. Activation of the prodrug can be monitored through fluorescence in real-time. We envision that thiolysis of the NBD amine could be readily used for development of other H2S-triggered prodrugs in the future.

A mitochondria-targeted red-emitting probe for imaging hydrogen sulfide in living cells and zebrafish.

Hydrogen sulfide (H2S) is an important endogenous signaling molecule with multiple biological functions. Based on the thiolysis of NBD (7-nitro-1,2,3-benzoxadiazole) amine, herein we rationally design and synthesize a new fluorescent probe 1 for the detection of mitochondrial H2S in living cells. Probe 1 displays bright red-emitting fluorescence after H2S activation (φ, 0.77). 1 shows higher selectivity and sensitivity for H2S than the red-emitting probe Rho-NBD (ChemBioChem, 2016, 17, 962). Moreover, 1 is water-soluble, cell-membrane-permeable, of low cytotoxicity and mitochondria-targeting, and can be employed for monitoring mitochondrial H2S in living cells.

Low doses of Paclitaxel repress breast cancer invasion through DJ-1/KLF17 signalling pathway.

Paclitaxel (taxol) is an important agent against many tumours, including breast cancer. Ample data documents that paclitaxel inhibits breast cancer metastasis while others prove that paclitaxel enhances breast cancer metastasis. The mechanisms by which paclitaxel exerts its action are not well established. This study focuses on the effect of paclitaxel, particularly the low doses on breast cancer metastasis and the mechanisms that regulate it. Current results show that, paclitaxel exerts significant cytotoxicity even at low doses in both MCF-7 and MDA-MB-231 cells. Interestingly, paclitaxel significantly inhibits cell invasion and migration, decreases Snail and increases E-cadherin mRNA expression levels at the indicated low doses. Furthermore, paclitaxel-inhibiting breast cancer metastasis is associated with down-regulation of DJ-1 and ID-1 mRNA expression level with a concurrent increase in KLF17 expression. Under the same experimental conditions, paclitaxel induces KLF17 and concurrently represses ID-1 protein levels. Our results show for the first time that paclitaxel inhibits breast cancer metastasis through regulating DJ-1/KLF17/ID-1 signalling pathway; repressed DJ-1 and ID-1 and enhanced KLF17 expression.